cyclic-gmp and Nephrosis

Isoprenaline-induced relaxation was investigated in aortas from control and daunomycin-induced nephrotic rats. In the endothelium-intact aortas precontracted with phenylephrine, the isoprenaline-induced relaxation and cyclic adenosine monophosphate (AMP) accumulation were significantly less in nephrotic rats than in control animals. Removal of the endothelium, pretreatment with methylene blue (MB), a guanylate cyclase inhibitor, or NW-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthase inhibitor, markedly reduced the relaxation induced by isoprenaline in nephrotic and control animals. The increase in cyclic AMP content induced by isoprenaline also was inhibited by these treatments. In addition, the difference in the isoprenaline-induced relaxation and cyclic AMP accumulation between nephrotic and control preparations was abolished by these treatments. The tissue cyclic guanosine monophosphate (GMP) level was not affected by isoprenaline. In the presence of zaprinast (Zap), a cyclic GMP phosphodiesterase inhibitor, the cyclic GMP level in the endothelium-intact tissues was significantly lower in nephrotic rats than in control animals. Removal of endothelium or pretreatment with MB or L-NAME markedly reduced cyclic GMP content in nephrotic and control animals. In the endothelium-denuded tissues, the isoprenaline-induced relaxation and cyclic AMP accumulation were markedly potentiated by a low concentration of nitroprusside (NP). In the endothelium-intact aortas precontracted with phenylephrine, relaxations induced by dobutamine, salbutamol, and forskolin in nephrotic rats were not significantly different from those in control animals. In the endothelium-intact aortas precontracted with KCl, the isoprenaline-induced relaxation also was significantly less in nephrotic rats than in control animals. Pretreatment with prazosin, but not yohimbine, abolished this difference. These results indicate that nephrosis decreases the relaxing response of the endothelium-intact aortas to isoprenaline. In addition, these results suggest that the endothelium-derived relaxing factor (EDRF) released from the endothelial cells markedly enhances isoprenaline-induced increase in the tissue level of cyclic AMP. The decreased relaxing response to isoprenaline in nephrotic rats may be caused by the decrease in the endothelial-dependent cyclic GMP release caused by alpha 1-adrenoceptor activation by isoprenaline.

Topics: Animals; Aorta, Thoracic; Cyclic AMP; Cyclic GMP; Endothelium, Vascular; In Vitro Techniques; Isoproterenol; Male; Nephrosis; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitroprusside; Rats; Rats, Sprague-Dawley; Vasodilation

The thoracic aorta was taken from nephrotic rats on the 40th day after a single i.v. injection of daunomycin (10 mg/kg). In the endothelium-intact aorta, the contractions induced by norepinephrine or B-HT 933, an alpha-2 adrenoceptor agonist, were significantly greater in nephrotic rats than in normal animals. However, such a difference was not observed in the KCl- or U46619-induced contractions. The difference in norepinephrine-induced contraction between nephrotic and normal preparations was enhanced by zaprinast, a cyclic GMP phosphodiesterase inhibitor. The contractions elicited by norepinephrine and B-HT 933 were potentiated by either removal of the endothelium or pretreatment with methylene blue, a guanylate cyclase inhibitor. The difference in the contractile response to these agonists between nephrotic and normal preparations was eliminated completely by either treatment. The cyclic GMP level in the endothelium-intact aorta in the presence of zaprinast was significantly lower in nephrotic rats than in normal animals. In the presence of zaprinast, norepinephrine, but not B-HT 933, caused an increase in the cyclic GMP level, which was abolished completely by pretreatment with prazosin, but not by yohimbine. These results suggest that the augmented contractile response to norepinephrine observed in nephrotic aorta may be due to the decrease in the stimulated release of endothelium-derived relaxing factor from the endothelial cells via the stimulation of endothelial alpha-1 adrenoceptors, whereas the augmented response to B-HT 933 may be due, at least in part, to the decrease in spontaneously released endothelium-derived relaxing factor.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adrenergic alpha-Agonists; Animals; Azepines; Cyclic GMP; Endothelium, Vascular; Male; Muscle Contraction; Nephrosis; Nitric Oxide; Norepinephrine; Potassium Chloride; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Sprague-Dawley; Thromboxane A2

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Cyclic GMP; Guanylate Cyclase; Kidney Cortex; Kidney Glomerulus; Kidney Tubules; Kinetics; Male; Nephrosis; Rats; Subcellular Fractions